Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease affecting motor neurons in the spinal cord, brainstem, and cortex. This disease clinically manifests as progressive muscular weakness and atrophy, leading to paralysis and death within 3-5 years of diagnosis. Treatments are only palliative. Neural transplantation may be able to restore lost neuromotor function and/or prevent motoneural degeneration. Because of the widespread degeneration of motor neurons in ALS, neural transplantation is not often considered a therapeutic option.
However, we recently demonstrated that the onset of motor dysfunction can be delayed and lifespan possibly extended when hNT Neurons are transplanted into the spinal cord of the transgenic mouse (SOD1, G93A) model of this disease. Since the hNT Neurons are postmitotic, terminally differentiated human neuronal-like cells, they must be transplanted directly into the injury site, not a practical treatment approach in ALS.
A better approach may be to administer a cell that migrates through the neural axis to the specific regions of neurodegeneration, such as neural stem cells. Most tissue used in neural transplantation protocols is now obtained from a human fetus, including the majority of stem cells. Ethical issues with the use of this fetal tissue make it necessary to locate alternative cell sources with the putative ability to migrate in the host to the site of injury or disease and differentiate into the required cell type. Stem cells from human umbilical cord blood (hUCB) may be preferable to other sources because they are obtained after delivery, so there is no risk to mother or child, and are more easily available than either bone marrow or neural stem cells.
The mononuclear cell fraction from human UCB is relatively rich in multipotent progenitors with extensive proliferation capacity. However, hematopoietic stem cells are only present at low levels (2% of mononuclear cells). Isolation and purification techniques of hematopoietic stem cells and other progenitors from human bone marrow and UCB have been developed, based on the expression of cell surface markers (CD34, CD38 Sca-1, thy-1, etc.) or on size and cell density, or other metrics. These techniques, however, are complex, too costly, and inefficient to be well suited to a clinical environment. In addition, cell populations resulting from these techniques are often heterogeneous with degraded functional activity and overlap between hematopoietic stem cells and mature progenitors.
The enzyme aldehyde dehydrogenase (ALDH) is found at relatively high levels in hematopoietic progenitors. Storms et al. (1999) suggest that “because high-level expression of ALDH appears to be an intrinsic property of a variety of stem cells, isolating primitive hematopoietic cells on the basis of ALDH activity may not be affected as significantly by the stem cell source, genetic background, or stem cell manipulation as other stem cell isolation methods.” This high level of ALDH activity may not be surprising given that retinoic acid (RA) is so critical in embryological development. Multiple isoforms of this enzyme are critical in the conversion of retinal or retinaldehyde to RA. The observation that these cells respond to RA+NGF (nerve growth factor) by differentiating into cells that express neural markers suggest that there may be an autocrine mechanism in this progenitor population that could be exploited.